2007 Grant - O'Barr

2007 New Investigator Research Grant

One of the hallmarks of Alzheimer's disease is the accumulation of a protein fragment called beta-amyloid. This fragment is suspected of disrupting cell-to-cell communication and causing nerve cell death in the brain. Beta-amyloid is clipped from its parent molecule, amyloid precursor protein (APP). Many Alzheimer treatment strategies have focused on preventing beta-amyloid production or removing already formed amyloid plaques. Preliminary clinical studies of such treatments have had mixed results, and they have often produced harmful side effects.

In preliminary studies, Stephen A. O'Barr, Ph.D., and colleagues have tested a potentially safer and more effective way of reducing brain beta-amyloid levels. Using mice genetically engineered to produce excess human APP, the researchers administered a drug treatment that increased the level of a certain thyroid hormone in the brain and activated an enzyme called insulin-degrading enzyme (IDE).

Results showed that the increased hormone levels decreased beta-amyloid production in the mice, while the activated IDE increased the animals' natural ability to clear existing beta-amyloid. These two effects led to a 60 percent reduction in overall beta-amyloid levels within the mice brains. The treatment also improved the animals' cognitive abilities.

For this proposed grant, Dr. O'Barr and colleagues will conduct more extensive studies with the mice to confirm their earlier results. The researchers hope to learn more about how their drug treatment affects (1) beta-amyloid plaque formation, (2) the number and size of existing plaques and (3) cognitive performance. Results could lead to clinical trials that test the drug's ability to alter the course of the disease and alleviate Alzheimer symptoms in human participants.